Re iew A icle
HMGB1 and Ex acellula His ones Signi ican ly Con ibu e o
Sys emic In lamma ion and Mul iple O gan Failu e in Acu e
Li e Failu e
Runkuan Yang,
1,2,3
Xiaoping Zou,
4
Jy ki Tenhunen,
1,5
and To Inge Tønnessen
3,6
1
Depa men o In ensi e Ca e Medicine, Tampe e Uni e si y Hospi al, Uni e si y o Tampe e, 10 Bio Ka u, 33014 Tampe e, Finland
2
Depa men o C i ical Ca e Medicine, Uni e si y o Pi sbu gh Medical School, 3550 Te ace S ee , Pi sbu gh, PA 15261, USA
3
Depa men o Eme gencies and C i ical Ca e, Oslo Uni e si y Hospi al, P.O. Box 4950 Nydalen, 0424 Oslo, No way
4
Depa men o Gas oen e ology, D um Towe Hospi al, Nanjing Uni e si y Medical School, 321 Zhongshan S ee ,
Nanjing 210008, China
5
Depa men o Su gical Science, Anes hesiology and In ensi e Ca e Medicine, Uppsala Uni e si y, 751 85 Uppsala, Sweden
6
Ins i u e o Clinical Medicine, Uni e si y o Oslo, Blinde n, 0316 Oslo, No way
Co espondence should be add essed o Runkuan Yang; [email p o ec ed]
Recei ed 25 No embe 2016; Re ised 27 Feb ua y 2017; Accep ed 8 May 2017; Published 13 June 2017
Academic Edi o : Jose C ispin
Copy igh © 2017 Runkuan Yang e al. This is an open access a icle dis ibu ed unde he C ea i e Commons A ibu ion License,
which pe mi s un es ic ed use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed.
Acu e li e ailu e (ALF) is he culmina ion o se e e li e cell inju y om a a ie y o causes. ALF occu s when he ex en o
hepa ocy e dea h exceeds he hepa ic egene a i e capaci y. ALF has a high mo ali y ha is associa ed wi h mul iple o gan
ailu e (MOF) and sepsis; howe e , he unde lying mechanisms a e s ill no clea . Eme ging e idence shows ha ALF pa ien s/
animals ha e high concen a ions o ci cula ing HMGB1, which can con ibu e o mul iple o gan inju ies and media e gu
bac e ial ansloca ion (BT). BT igge s/induces sys emic inflamma o y esponses synd ome (SIRS), which can lead o MOF in
ALF. Blockade o HMGB1 significan ly dec eases BT and imp o es hepa ocy e egene a ion in expe imen al acu e a al li e
inju y. The e o e, HMGB1 seems o be an impo an ac o ha links BT and sys emic inflamma ion in ALF. ALF pa ien s/
animals also ha e high le els o ci cula ing his ones, which migh be he majo media o s o sys emic inflamma ion in pa ien s
wi h ALF. Ex acellula his ones kill endo helial cells and elici immunos imula o y effec o induce mul iple o gan inju ies.
Neu aliza ion o his ones can a enua e acu e li e , lung, and b ain inju ies. In conclusion, HMGB1 and his ones play a
significan ole in inducing sys emic inflamma ion and MOF in ALF.
1. Backg ound
Acu e li e ailu e is defined as a clinical synd ome cha -
ac e ized by li e inju y wi h e idence o coagulopa hy
and any deg ee o al e ed men al s a us in a pa ien wi h-
ou p eexis ing li e disease and du a ion o illness less
han 26 weeks [1–3]. The e iology a ies wi h geog aphy.
Hepa o ophic i uses a e he mos common cause o ALF
in de eloping coun ies [4, 5]; d ugs a e he mos common
cause o ALF in he indus ialized na ions [4, 6]. The mo -
ali y o ALF is as high as 40–50%, and he cause o dea h
in ALF includes b ain he nia ion due o aised in ac anial
p essu e (35%) and sepsis wi h mul iple o gan ailu e [3].
Li e ansplan a ion is he only he apeu ic in e en ion
wi h p o en su i al benefi in pa ien s wi h i e e sible
ALF [2]. ALF pa ien s a e p one o in ec ion due o he
immunologic de ec and he high-dependency ca e hey
equi e [7]. Be ween 39% and 57% o ALF pa ien s expe-
ience bac e ial in ec ion [8]. ALF has a high a e o
in ec ion wi h g am-nega i e en e ic bac e ia in animal
model [9]. G am-nega i e and g am-posi i e bac e ia can
elici sepsis [7]. In ec ions and/o he esul ing SIRS a e
impo an con ibu ing ac o s ha wo sen hepa ic ence-
phalopa hy (HE) [8]. ALF is associa ed wi h MOF and a
high incidence o sepsis (35.7%), which con ibu es o
23.1% o he mo ali y [7]; howe e , he unde lying
Hindawi
Media o s o Inflamma ion
Volume 2017, A icle ID 5928078, 6 pages
h ps://doi.o g/10.1155/2017/5928078
mechanism is s ill no clea . Ea ly inflamma o y media o s
(such as TNF-α, IL-6, and IL-1β) a e ce ainly in ol ed in
he pa hogenesis o ALF [10]; howe e , hese ea ly cy o-
kines ha e limi ed clinical significance due o he na ow
he apeu ic window. In con as , HMGB1 is a la e media-
o o le hal sys emic inflamma ion [11], and HMGB1 has
a p olonged he apeu ic window as compa ed o hose
ea ly inflamma o y cy okines; ci cula ing TNF-αand IL-6
a e ele a ed o 5 days a e he onse o sepsis, and se um
HMGB1 le els a e inc eased om day 7 un il a leas day
28 [12]. Eme ging e idences indica e ha HMGB1 is an
impo an ac o ha links gu BT and sepsis, and ex a-
cellula his ones a e also impo an ac o s ha signifi-
can ly con ibu e o MOF in ALF. In his manusc ip , we
e iew he cu en unde s anding o HMGB1 and his ones
in ALF.
2. The Role o HMGB1 in ALF
2.1. HMGB1 is a Typical Ala min. Endogenous dange -
associa ed molecula pa e ns (DAMPs) a e also known as
ala mins, which signal cellula damage and ac i a e he
inna e immune sys em [13]. Ala mins sha e he ollowing
ea u es: (a) apid elease om cells in esponse o in ec ion
o issue damage, (b) chemoa ac ion and ac i a ion o
an igen-p esen ing cells, and (c) ac i a ion o inna e and
adap i e immuni y [14]. HMGB1 is a ypical ala min [14].
2.2. Passi e Release. HMGB1 can be passi ely eleased by
nec o ic/damaged cells o ac i ely sec e ed by immuno-
compe en cells [15]. Unde nec o ic condi ion, con en s
o he cy osol a e dispe sed in o he ex acellula space
due o cellula dis ess o damage [16]. In nec o ic cells,
HMGB1 dissocia es om ch oma in and is eleased om
cells o igge inflamma ion. Howe e , HMGB1 emains
bound o ch oma in and ails o p omo e inflamma ion
in cells unde going apop o ic o p og ammed cell dea h,
in which cy osolic con en s a e seques e ed and no “seen”
by inna e immune cells [16].
2.3. Ac i e Sec e ion. In esponse o p oinflamma o y s imuli
such as LPS, HMGB1 can be ac i ely sec e ed by immuno-
compe en cells. This ac i e sec e ion occu s h ough a
wo-s ep p ocess. Fi s , HMGB1 is ansloca ed ou o
he nucleus o he cy oplasm a e JAK/STAT1- egula ed
hype -ace yla ion o lysine esidues loca ed in he A and
B box domains [17]. Once in he cy oplasm, HMGB1 is
ac i ely sec e ed [17]. The ac i e sec e ion o HMGB1
ollows a nonclassical, esicle-media ed pa hway [18].
2.4. Redox S a e and Ex acellula Func ions. HMGB1 con-
ains h ee conse ed edox-sensi i e cys eines (C23, C45,
and C106), and pos ansla ional modifica ion (oxida ion)
o hese cys eines de e mines he bioac i i y o ex acellula
HMGB1 [19]. The cy okine-s imula ing ac i i y o HMGB1
equi es C23 and C45 o be in a disulfide linkage, while
C106 emains in a educed s a e. This disulfide HMGB1
can bind and signal ia TLR4/MD-2 complex o induce
cy okine elease in mac ophage [19]. Mo eo e , binding o
HMGB1 o TLR4 depends on educed Cys106 [20]. I all
h ee cys eines a e in educed o m, his all- hiol HMGB1
has chemo ac ic ac i i y. This o m is p esen unde basal
condi ions. Unde inflamma o y condi ions, his all- hiol
HMGB1 is eleased and o ms a he e ocomplex wi h he
chemokine CXCL12 o in e ac wi h he chemokine ecep o
CXCR4 o p omo e cell mig a ion, bu no inflamma o y
cy okine sec e ion. The hi d o m o HMGB1 occu s unde
a s a e o comple e oxida ion whe ein each cys eine is ully
oxidized o a sul onyl o m and is no associa ed wi h any
biological unc ion [19]. Hype ace yla ion o HMGB1 shi s
i s equilib ium om a p edominan nuclea loca ion owa d
a cy osolic and subsequen ex acellula p esence. Hence,
pos ansla ional modifica ions o HMGB1 de e mine i s
ole in inflamma ion and immuni y [19].
2.5. ALF Releases HMGB1 as a Signal o Inflamma ion. ALF
occu s when he ex en o hepa ocy e dea h exceeds he
hepa ic egene a i e capaci y [21], and he mode o he cell
dea h ypically ollows one o he wo pa e ns: nec osis o
apop osis [21]. In a clinical ial, HMGB1 ep esen s he
ci cula ing indica o o nec osis du ing ace aminophen hep-
a o oxici y; ull-leng h and caspase-clea ed ke a in-18 a e
ci cula ing ma ke s o nec osis and apop osis; hype -
ace yla ed HMGB1 is a se um indica o o py op osis and
immune cell ac i a ion [22, 23]. Ele a ions in plasma
HMGB1 and ke a in-18 can se e as mechanis ic bioma ke s
o p o ide ea ly and sensi i e de ec ion o ace aminophen-
induced acu e li e inju y a fi s p esen a ion o a hospi al
[22]. Inc eased o al and ace yla ed HMGB1 and ull-
leng h ke a in-18 a e associa ed wi h wo se p ognosis
du ing clinical ace aminophen hepa o oxici y [23]. HMGB1
can be eleased eadily om nec o ic o damaged cells o
se e as a signal o inflamma ion [16, 24]. HMGB1 plays
an impo an ole in modula ing inflamma o y cascade in
ac i a ed mac ophages: HMGB1 s imula es mac ophages
o elease TNF-αand IL-6 [20, 25]. HMGB1 is a po en
media o o sys emic inflamma ion in sepsis [26].
2.6. HMGB1 Con ibu es o Mul iple O gan Inju ies. HMGB1
con ibu es o li e inju y in expe imen al ischemia-
epe usion [27]. Exogenous HMGB1 injec ion can induce
e iden li e inju y in mice [28]. HMGB1 impai s hepa ocy e
egene a ion and blockade o HMGB1 imp o es hepa ocy e
egene a ion in mice challenged wi h ace aminophen o e -
dose [29]. A pa ly humanized an i-HMGB1 monoclonal
an ibody a enua es ace aminophen hepa o oxici y and
pos inju y inflamma ion in mice [30]. HMGB1 is eleased
in o he se um a ea ly s age o D-galac osamine/LPS-
induced ALF, and HMGB1 ac s syne gis ically wi h TNF-α
o p omo e he inflamma o y li e inju y; his de imen al
effec can be e e sed by monoclonal an ibodies agains
HMGB1 and TNF-α[31]. Inhibi ion o sphingosine kinase-
1 amelio a es expe imen al ALF by educing high-mobili y
g oup box 1 cy oplasmic ansloca ion in li e cells [32].
HMGB1 con ibu es o enal ischemia- epe usion inju y
[33], sepsis-induced kidney inju y [34], and se e e acu e
panc ea i is- ela ed kidney inju y [35]. HMGB1 also signifi-
can ly con ibu es o hemo hagic shock- ela ed acu e lung
2 Media o s o Inflamma ion
inju y (ALI) [36], hype oxia-induced ALI [37], and se e e
acu e panc ea i is- ela ed ALI [38].
2.7. HMGB1 Con ibu es o Gu Mucosal Inju y and Media es
Gu BT in ALF. Gu mucosal inju y and in es inal BT in ALF
is pa icula ly impo an because he in es ine is he bigges
ese oi o bac e ia in he body and leakage o bac e ia o
mic obial p oduc s, no ably LPS, om he lumen o he gu
in o he sys emic ci cula ion, leads o ini ia ion o amplifica-
ion o a sys emic inflamma o y esponse synd ome and
mul iple o gan dys unc ion synd ome (MODS). The e o e,
he leaky gu is hough o be he “mo o ” ha d i es he
de elopmen o MODS [39].
The se um HMGB1 concen a ions a e significan ly
inc eased in mice challenged wi h ace aminophen o e dose
[29, 40]. ALF pa ien s also ha e high concen a ions o ci cu-
la ing HMGB1, and he ci cula ing HMGB1 le els a e associ-
a ed wi h disease se e i y [41, 42]. The ci cula ing HMGB1
con ibu es o gu mucosal hype pe meabili y and induces
e iden BT in expe imen al hemo hagic shock and epe u-
sion [43], and exogenous HMGB1 injec ion can induce gu
hype pe meabili y and BT in mice [28]. Excep om he
ci cula ing HMGB1, bile HMGB1 migh also significan ly
con ibu e o in es inal mucosa inju y and induce e iden
BT in ALF, because hepa i is E i us- ela ed ALF is associ-
a ed wi h significan ly inc eased ci cula ing LPS [44], and
LPS injec ion educes 40% o bile flow in a s [45]; adequa e
bile is equi ed o main ain gu epi helial igh junc ion and
in es inal bac e ial homeos asis [46]; dec eased gu luminal
bile olume no only impai s in es inal igh junc ion bu
also changes in es inal bac e ial homeos asis o acili a e
BT [46, 47]. In addi ion, LPS injec ion ( o no mal animals)
ma kedly inc eases bile TNF-αand HMGB1 le els, which
can induce gu mucosal hype pe meabili y and e iden BT
in mice [45], and his de imen al effec can be e e sed by
neu aliza ion o he bile HMGB1 [45].
Expe imen al hepa o oxici y is associa ed wi h high inci-
dence o gu de i ed g am-nega i e bac e ial in ec ion [9, 40].
Ace aminophen o e dose can induce e iden gu BT and
se e e in es inal mucosal inju y in mice [40], and gu bac e ia
can adhe e o he inju ed mucosa, which is necessa y bu no
sufficien o induce gu BT [40], because blockade o HMGB1
educes 85% o gu BT, bu i does no dec ease gu mucosal
pe meabili y in expe imen al ace aminophen o e dose [40].
This indica es ha BT is media ed (a leas pa ly) by
HMGB1 and BT is likely an ac i e “ anscellula ”p ocedu e
in which HMGB1 is also needed.
2.8. BT Induces/T igge s Sys emic Inflamma ion, Which Leads
o MOF in ALF. Gu BT (o gu -de i ed LPS) induces/ igge s
sys emic inflamma ion in c i ical illness [48, 49]. SIRS can
lead o MOF in ALF [7]. Sepsis is a ypical example o
SIRS igge ed by in ec ion [50]. The e o e, HMGB1 seems
o be an impo an ac o ha links BT and SIRS in ALF.
3. The Role o Ex acellula His ones in ALF
3.1. ALF Pa ien s/Animals Ha e High Concen a ions o
Ci cula ing His ones. ALF has a la ge numbe o hepa ocy e
dea h [21]. The nec o ic issue/ he dying hepa ocy es
elease HMGB1 and his ones [50], which can con ibu e
o he high concen a ions o ci cula ing his ones in ani-
mals challenged wi h concana alin A and ace aminophen
o e dose o induce wo diffe en acu e a al li e inju y
models [50]. Ci cula ing his ones a e significan ly inc eased
in ALF pa ien s and in pa ien s wi h HBV- ela ed acu e-on-
ch onic li e ailu e, and he le els o ci cula ing his ones
a e co ela ed wi h disease se e i y and mo ali y [51, 52].
ALF pa ien s also ha e ele a ed plasma his one-associa ed
DNA le els [53]. DAMPs ac i a e inna e immune cells in
he li e and he ci cula ion, subsequen ly leading o issue
inflamma ion and SIRS [53, 54].
3.2. Ex acellula His ones Con ibu e o Mul iple O gan
Inju ies in ALF. His ones a e impo an s uc u al elemen s
o nuclea ch oma in and egula e gene ansc ip ion [54];
howe e , ex acellula his ones a e cell oxic o hos cells
[50, 54] and elici immunos imula o y effec ha can induce
mul iple o gan inju ies [50, 53–55]. Ci cula ing his ones
exace ba e inflamma ion in mice wi h ALF [56]. The se a
(con aining high le els o his ones) om ALF pa ien s can
induce L02 cell (hepa ocy e) dea h and s imula e U937 cells
(monocy es) o elease inflamma o y cy okines; hese de i-
men al effec s can be abolished by non-an icoagulan hepa in
ha can bind his ones, sugges ing ha ci cula ing his ones
migh be he majo media o s o sys emic inflamma ion
and cellula inju y in pa ien s wi h ALF [51]. The ci cula ing
angiopoie in-2 le els, a ma ke o issue endo helial dys unc-
ion and leakage, a e ma kedly inc eased in ALF pa ien s
[53], and his migh be due o he oxici y o ex acellula his-
ones in ALF pa ien s. Ex acellula his ones con ibu e o
acu e a al li e inju y ia TLR 2 and TLR4 ecep o s, and
neu aliza ion o his ones can amelio a e a al li e inju y in
mice [50]. The le els o ci cula ing his ones a e significan ly
highe a e li e ischemia/ epe usion, he endogenous
his ones unc ion as ala mins in s e ile inflamma o y li e
inju y h ough oll-like ecep o 9, and neu aliza ion o
his one significan ly p o ec s agains inju y [57]. Ex acellu-
la his ones can induce mic o ascula endo helial inju y,
and he TLR2/4-media ed inflamma ion leads o acu e ubu-
la nec osis in expe imen al acu e kidney inju y [58, 59].
Ex acellula his ones can inju e endo helial cells o cause
mic o ascula h ombosis and hemo hage in expe imen al
acu e lung inju y [60]. His ones also con ibu e o expe i-
men al acu e b ain inju y, and neu aliza ion o his ones
can educe he in a c size [61]. His one H4 and inc eased
ci cula ing neu ophil ex acellula aps (NETs) can ac i a e
pla ele s; his may cause mic o ascula h ombosis in sepsis
[50, 55, 59, 62]. HMGB1 may induce he same biological
esponse [63]. Ex acellula his ones kill endo helial cells
and a e one o he majo media o s o dea h in sepsis [55].
4. Conclusions
HMGB1 and ex acellula his ones play a significan ole in
inducing sys emic inflamma ion and MOF in ALF; neu ali-
za ion o HMGB1 and his ones may p esen a no el he apy
o ea ALF.
3Media o s o Inflamma ion
A g aphical abs ac is p o ided as he Supplemen a y
ma e ial a ailable online a h ps://doi.o g/10.1155/2017/
5928078.
Abb e ia ions
ALF: Acu e li e ailu e
MOF: Mul iple o gan ailu e
SIRS: Sys emic inflamma o y esponse synd ome
BT: Bac e ial ansloca ion
HMGB1: High mobili y g oup box 1
NETs: Neu ophil ex acellula aps
DAMP: Damage-associa ed molecula pa e n
TLR: Toll-like ecep o
APAP: Ace aminophen
MODS: Mul iple o gan dys unc ion synd ome
MD-2: Myeloid diffe en ia ion ac o 2
LPS: Lipopolysaccha ide
D-GalN: D-galac osamine
Sphk1: Sphingosine kinase 1.
Con lic s o In e es
The au ho s decla e ha hey ha e no compe ing in e es s.
Au ho s’Con ibu ions
Runkuan Yang designed and d a ed he manusc ip .
Xiaoping Zou ca ied ou he li e a u e sea ch and d a ed
he manusc ip . To Inge Tønnessen d a ed and e ised
he manusc ip .
Acknowledgmen s
This in es iga ion was pa ly suppo ed by Sig id Juselius
Funding in Finland and Sou h-Eas e n No way Regional
Heal h Au ho i y, G an no. 2013121.
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